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Southern African Human Genome ProjectGenes are the language of biology. The language is written in a code which is made of four letters only; the nucleotides adenine (A), thymine (T), cytosine (C) and guanine (G). The sequence or arrangement of these nucleotides determines what the gene encodes, as would an arrangement of letters determine what a word means and what the message says. Small differences in the arrangement of the letters can alter the meaning. A single nucleotide polymorphism, or SNP, is one example of small changes or variation in the DNA sequence altering the meaning. This would be similar to changes in one letter in a word altering the meaning, for example “cat” versus “bat”.

Spelling is everythingThe small differences in the order of the letters are what make every person unique. It gives one person red hair and another brown; it enables one person to resist an infection, while another person succumbs.

Every person has the same genes, however each person will have a unique “spelling” or variation within their genes which makes those genes work slightly differently. The language within a person’s genome (or their total genetic make-up) reflects that of the community from which they come. Close relatives share more similarity in their genes than friends and neighbours. People originating from one region share more similarity in their genes than people coming from distant regions.

The southern Africa dialectThe peoples of southern Africa have lived together for thousands of years. During this time they have created a special southern African genetic dialect, a collection of nucleotide combinations, SNPs, which occur over and over again in people living in the region. Some of these SNPs occur exclusively in people from this area; most of them are found elsewhere as well, but the relative frequencies of occurrence may vary.

The international dictionaryScientists are keen to learn all the SNPs and record them in the equivalent of a dictionary. No one knows for sure how many SNPs will be found, but already over 38 million unique and validated SNPs have been identified. Many more rare SNPs are likely to be found over the next few years as more and more whole genomes from individuals in different populations are sequenced in their entirety. This “dictionary” will be used to better understand how the body functions, as well as what happens when things go wrong.

One of the major purposes of the dictionary is to improve diagnosis and treatment of disease. Today medicines are designed to work for “Mr/Mrs Average”. This means that when you take any medicine, it might work very well but it also might not. In fact, some medicines actually end up making a person ill, because that person’s body doesn’t handle the medicine appropriately, leading to toxicity. In other cases, the medicine may have little or no effect on the outcome of the disease. The medicines of the future will be designed specifically for the sick individual. This type of treatment is referred to as personalised medicine. It is based on the principles of pharmacogenomics, i.e. drugs for YOUR genome. In the future, when you get ill, tests will be done to understand why YOU are ill, and then a medicine that will address YOUR specific problem will be prescribed.

The dictionary to dateThrough an international project called the 1000 Genomes Study, the whole genomes several 1000 individuals from many different world populations are being sequenced with the data from several 100 already available in public databases. Scientists are therefore deciphering the genetic language of the genes of thousands of people. All the common SNPs of the particular population groups that have been sequenced have already been added. But SNPs that have a frequency of less than 1 % in the world population are frequently being identified as more genomes are being sequenced and recorded on a regular basis.

The problem with the current “dictionary” or database, is that very few of the people

lifestyle, and physical activity to lower their overall risk. Alzheimer’s disease is progressive and symptoms typically manifest late in the disease, awareness and heightened vigilance will help affected individual’s access to early intervention therapies, potentially slowing disease progression.

Although more and more whole genomes are being sequenced in individuals whose health history has been documented in much detail, we still are a long way to understanding the impact of genetic variation in predisposing us to many diseases. This is especially true for complex and multifactorial diseases of late onset like diabetes, hypertension and asthma, to name but a few.

In the future a better understanding of the combination of SNPs (as well as other types of DNA variation) and risk behaviours (including smoking, diet, drinking, etc.) will offer insight to lead towards personalised preventative medicine, enabling individuals to take charge of their own health (in consultation with health care providers to guide them) so that they can avoid or minimize lifestyle diseases such as heart attacks, stroke and diabetes.

The Project will do more than just read genomesThe size and scope of the SAHGP will do far more for southern Africa than just create a southern African genomic dictionary.

In order to handle the vast workload, southern African scientists will need to develop the necessary skills and infrastructure to generate and process the large amount of data.

More people will need to be trained in genomic research, particularly in the field of bioinformatics. Initiatives aimed at equipping young southern African scientists with these highly sought after skills will make them more marketable as individuals and strengthen the scientific community of the country as a whole.

The future global economy is expected to be driven by developments in the field of biotechnology. The South African government is committed to transforming South Africa into a knowledge-driven economy, capable of commercialising the results of research to build a better world for her citizens. Researchers able to acquire and use the fruits of the genomic revolution will help accelerate economic growth through the establishment of biotechnology based businesses.

Cradle of Humankind unpluggedSouth Africa’s World Heritage Site, the Cradle of Humankind is the location of some of the oldest hominid fossils ever found, some dating back as far as 3.5 million years ago. The presence of these fossils gives the southern African region the highest time depth of human history. The degree of

genetic diversity within current populations suggests that modern Homo sapiens originated in southern Africa rather than East Africa, as has been previously postulated.

Unraveling details of the southern African genome will allow geneticists and anthropologists to compare the construction of the genome across diverse populations, to determine the degree of kinship between them and their evolutionary history. The SAHGP will contribute to advances in the field of molecular anthropology and provide insights into ancient human migrations within and from Africa.

Could the genome project lead to discrimination?The project will not be creating a Zulu or a Tswana dictionary, it is creating a registry of the genes of the rainbow nation. As a nation, we are a mixture of tribes, tongues and SNPs. The focus is not only on understanding where the genetic variants came from, but documenting their presence and nature and the impact that they are having on the health of the individuals carrying them. The identity of the individuals whose genomes are included in the database will not be made known – all that we will know is that the genome lived on the southern tip of Africa at the beginning of the 21st century.

Our genomic heritage is protected by our constitution. As genomic technologies unfold, South African lawmakers will pass the necessary laws to safeguard privacy and security of genetic information.

Could parents “choose” their babies’ SNPs?Today it is possible for parents who are worried about their child suffering from a severe genetic disease to test whether the unborn fetus is carrying the genetic variant, and then to make a decision on terminating the pregnancy.

Genetic variants help to determine the likelihood that someone will develop a particular disease. Identifying a SNP in an unborn fetus would provide parents with guidance on how to help it grow up to be healthy. SNPs results are not currently used as medical grounds for abortion.

This fact sheet has been reviewed by independent experts and has followed

SAASTA’s Scientific Editorial Process. www.saasta.ac.za

Last updated in November 2013

whose genomes have been described came from southern Africa, so the SNPs that are unique to southern Africans may not be entered into the dictionary at all.

Even when the SNPs are not unique, it will be difficult to know if they occur often or rarely in southern African populations - information which is important when designing treatment strategies for the region.

Southern Africans who are in the dictionary.....International and southern African researchers have already contributed some southern African information to the database.

In February 2010, a team led by Stephan Schuster from Penn State University published their results of the genome sequence of five southern Africans. Only one person was a South African, all be it a very famous South African, namely Archbishop Desmond Tutu. The others were citizens of Namibia. The Namibians represented a very distinct group of people who live in the Kalahari desert – the Bushmen or San. The four individuals selected for this study came from different areas of the Kalahari.

The sequencing of these five genomes highlighted the genetic variance and the need to include more Africans in the global database. These five people introduced 1.2 million new SNPs to the global database. Despite the fact that they all lived in southern Africa, their genomes showed at lot of variation. In fact, there were more differences between them than between someone who comes from Europe and someone who comes from Asia.

In May 2010, a group from Stellenbosch University published their results of their genome-wide analysis of the genetic makeup of the Coloured population in the Western Cape, studying 959 individuals from the Western Cape. They showed that the major ancestry of this population was Khoesan (32-43%), Bantu-speaking Africans (20-36%), European (21-28%), with a small Asian component (9-11%).

More recently in 2012, a research team from the University of Pennsylvania sequenced the whole genomes of five individuals from each of the Khoesan-speaking Hadza and Sandawe from Tanzania and from the Pygmies from Cameroon. They identified many novel targets that play a role in immunity, reproduction, metabolism and height that may have shaped the adaptation of hunter-gatherer populations. This work contributes to efforts to reconstruct human evolutionary history.

Also in 2012, a team led by researchers at Uppsala University published their results of the genotyping of 220 Southern Africans. They showed that the Khoesan population diverged genetically from other human populations over 100 000 years ago, but structure within the Khoesan dates back to about 35 000 years ago, and suggest that modern anatomy developed before humans diversified. Their study suggested that genomic studies in Africa hold some of the keys to the main questions surrounding modern human origins.

not junk, since it contains the genetic switches which are responsible for regulating the switching on andoff of genes. The process of turning genes on and off is tightly controlled and critical for normal development and functioning. These regions of the DNA are increasingly being implicated in disease. The SNPs located in these regions may prove to be important.

Creating the southern African dictionary is a very big jobThe technologies to sequence the human genome have advanced significantly, so creating the dictionary is easier to do. But it is still an enormous job, which will require a significant outlay of both money and manpower. Scientists, government and industry are coming together to tackle the job of creating a southern African genetic dictionary. The job will be done by southern Africans for southern Africans.

The Southern African Human Genome Programme (SAHGP) is still in the planning phases and will be structured as an independent or semi-independent entity to enable it to manage the partnerships within southern Africa, as well as collaborate with other African initiatives and international collaborators. The team consists of a multi-disciplinary panel. It will include scientists, medical practitioners, biostatisticians, ethicists, government representatives, lawyers and industry representatives.

The core group members of SAHGP include • Soraya Bardien-Kruger and Louise Warnich (University of Stellenbosch),

• Alan Christoffels (University of the Western Cape),

• Jeffrey Mphahlele and Philippus Venter (University of Limpopo),

• Michael Pepper (University of Pretoria),

• Raj Ramasar (University of Cape Town),

• Michèle Ramsay and Himla Soodyall (National Health Laboratory Services/Wits University)

• Jasper Rees (University of the Western Cape/Agricultural Research Council)

Southern African Human Genome Project

The SAHGP will bring researchers from universities, science councils and industry together to

work on unraveling the complete sequence of A, T, C and Gs

of a collection of

Southern Africa needs its own dictionaryDisease patterns in southern Africa differ from that seen in the other parts of the world. For example:

• Despite having very high rates of infection with the cancer-causing stomach bacterium, Helicobacter pylori, we don’t have high rates of gastric cancer. It is so strange that scientists have referred to it as the African enigma. When gastric cancer does occur, the gene patterns in the tumours are different to those seen in Europeans.

• On the other hand, HIV/AIDS has been devastating in southern Africa. Southern Africans don’t handle the virus well and the anti-retroviral drugs used to fight HIV infections are less effective and more toxic to southern Africans.

The distinctive southern African genetic language, coupled with distinct disease patterns, suggest that understanding genetic variation in southern Africans is imperative.

If treatment in the future will be developed based on genetic make-up, there will be few medicines designed specifically for the southern African genetic profile unless the profile is described and documented. The medicines that will be offered to southern Africans will be geared towards European genomes and may not provide optimum care.

Why only a dictionary will doAt present some of the SNPs which influence the patterns of disease have been identified, but the searches are constrained by the fact that only the more obvious places have been looked into. For example, while the search for clues to the HIV problem has looked at genes associated with immunity and proteins implicated in the HIV infection, the response to HIV is dependent on a host of other factors. Being able to only gather small pieces of the picture makes the job at hand difficult and would not expose the unexpected. In an ideal world with unlimited resources, the sequencing of whole genes for all study populations would be first prize.

Ideally, the BIG picture needs to extend beyond investigations targeted to only the small percentage of DNA which codes for proteins. A search of the whole genome includes both the coding and the non-coding areas of the DNA, sometimes mistakenly referred to as the “junk DNA”. Junk DNA is definitely

southern African

genomes.The sequencing will be performed using

high throughput DNA sequencing platforms, either in South Africa or from service providers abroad. These machines are able to systematically comb through the genetic material and record the sequence of the nucleotide letters. They will generate huge amounts of data, which will need to be analysed and collated to make it user friendly. The huge volumes of data will be assembled in a database and form part of the national heritage. The data itself cannot be patented, as patents cannot be applied to naturally occurring genes in humans or any other naturally occurring organism.

Medical benefits of SAHGPSouth African (and international) scientists and entrepreneurs will be able to access the data and use it to do further studies. The advanced studies will reveal the meaning behind the SNPs, specifically how they contribute to health and/or disease.

Any new medicines and diagnostics developed using this advanced information will more than likely be patented. Using a pharmacogenomic approach will mean the medicines will work better, be safer and cost less to develop, so local communities will reap the benefits.

Developing new medicines and diagnostics take a long time. On average it takes 12-13 years to take a new medicine from an idea in the laboratory to a pill or injection given to a patient. The SAHGP is an investment in the future health of the nation, not a quick fix. The value of the regional database will grow over time, contributing to better health for both current and future generations of southern Africans.

Deciphering SNPs will also help to make current medicines safer and more effective. The response to a drug depends on the chemical getting to the right place, at the right time, at the right concentration. SNPs and genetic variations influence how an individual responds to a drug, so physicians will be able to choose the best drug for a patient and get the dose just right for that patient, avoiding toxicity and ensuring efficacy.

Health benefits of SAGHPSNPs may not only help diagnose and treat diseases, but could also help people to avoid and reduce the risk of diseases for which they have a predisposition. Researchers have already discovered two important SNPs which significantly increase the risk of developing Alzheimer’s disease. The two SNPs are found in Apolipoprotein E gene, causing three possible alleles or gene variants - E2, E3 and E4 - for the gene. The alleles differ by one DNA base, but inheriting one or more copies of E4 alters the structure and function of its protein enough to make the disease more likely, but not always symptomatic.

A person who is aware of the fact that they are at a higher risk of Alzheimer’s disease could adjust their behaviour, diet,